盐城 2008-8-4 19:56
Cell：发现新的细胞超氧生成事件
活性氧族（reactive oxygen species, ROS）是含氧并具有高反应活性的一类自由基或分子，其中超氧阴离子是一种高活性氧自由基，并且是细胞内ROS的最初生成形式，广泛参与细胞信号调节、代谢、生存和凋亡，而氧化应激是衰老和多种重大疾病如心肌梗死、脑卒中、糖尿病、老年痴呆症等重要机制之一。
在科技部973计划等的资助下，北京大学分子医学研究所程和平教授研究组与合作者为共同第一作者和共同责任作者的论文“单个线粒体超氧炫”，于7月25日在《细胞》（Cell）杂志以配图 “Featured Article”形式发表。
研究发现一种新的细胞超氧生成事件，并命名为“超氧炫”（superoxide flashes）。超氧炫是细胞内（含102-104个线粒体）单个线粒体中超氧信号的瞬时爆发现象，这是首次在活体细胞中观测到局部、间歇性、量子化超氧的产生。超氧炫为线粒体膜通透性转运孔道(mPTP)开放所触发，与线粒体电子传递链活性密切相关。上述发现是基于发明了一种新颖的高特异性超氧指示剂，即基因编码的、定位于线粒体的可用于实时测量的荧光蛋白。
上述工作对自由基和线粒体研究领域有三方面的意义，一是找到了新的ROS信号指示剂，二是超氧炫可作为氧化应激相关疾病的生物标记物，三是对生理和病理状况下mPTP和电子传递链功能有了新认识。
推荐原始出处：
Cell，Vol 134, 279-290，Wang Wang，Heping Cheng
Superoxide Flashes in Single Mitochondria
Wang Wang,1, Huaqiang Fang,4 Linda Groom,5 Aiwu Cheng,2 Wanrui Zhang,4 Jie Liu,4 Xianhua Wang,4 Kaitao Li,4 Peidong Han,4 Ming Zheng,4 Jinhu Yin,3 Weidong Wang,3 Mark P. Mattson,2 Joseph P.Y. Kao,6 Edward G. Lakatta,1 Shey-Shing Sheu,5 Kunfu Ouyang,7 Ju Chen,7 Robert T. Dirksen,5 and Heping Cheng4,
1 Laboratories of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
2 Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
3 Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
4 Institute of Molecular Medicine and National Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing 100871, China
5 Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA
6 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
7 Department of Medicine, University of California, San Diego, CA 92093, USA
Summary
In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed “superoxide flashes.” Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases.
terry 2008-8-4 20:28
程和平 教授
Ph.D. 博士生导师
长江特聘教授
钙信号实验室主任
联系电话：010-6275-8383
E-mail: chengp@ pku.edu.cn
通讯地址：北京大学英杰交流中心338室 100871
1980-1987就学于北京大学力学系，获学士和生物工程专业硕士学位，同时辅修生物学系生理学专业，获第二学士学位；1987-1989 任教于北京大学无线电电子学系；1990-1995 留学美国马里兰大学(Baltimore)医学院生理系，获博士学位。曾任美国NIH老年研究所心血管科学实验室钙信号研究室主任，资深研究员(Senior Investigator, tenured)。1998在北京大学组建细胞钙信号研究室，获国家杰出青年科学基金。2000获聘教育部长江特聘教授。现全职担任北京大学分子医学研究所钙信号实验室主任。
程和平教授迄今发表论文近百篇，其中8篇刊于《Science》、《Nature》和《Cell》。他于1993年在马里兰大学Jon Lederer实验室发现细胞内钙释放的最小单位，并命名为“钙火花”(Calcium Sparks)，论文在《Science》上发表。2004年该论文被誉为100年来最杰出的10篇心肌论文之一（Physiology News，2004，57：9-11）。1999年，美国科学院Knox Chandler院士在《Journal of General Physiology》上展望这方面的研究时，称之为Sparkology（钙火花学）。近年来程和平教授的研究兴趣拓展到ROS信号转导及生物信号复杂系统研究。
代表文章：
1. Cheng, H., Lederer, W.J., Cannell., M.B., 1993, Calcium sparks: The elementary events underlying excitation-contraction coupling in heart muscle. Science 262, 740-744
2. Cheng, H., Fill, M., Valdivia, H.H., Lederer, W.J., 1995, Models of calcium release channel adaptation, Science 267, 2009-2010
3. Cannell, M.B., Cheng, H., Lederer, W.J., 1995, The control of calcium release in heart muscle. Science 268, 1045-1050
4. Nelson, M.T., Cheng, H., Rubart, M., Santana, L.F., Bonev, A., Knot, H., Lederer, W.J., 1995, Relaxation of arterial smooth muscle by calcium sparks. Science 270, 633-637
5. Klein, M.G., Cheng, H.*, Santana, L.F., Lederer, W.J., Schneider, M.F., 1996, Discrete sarcomeric calcium release events activated by dual mechanisms in skeletal muscle. Nature 379, 455-458 (* the corresponding author)
6. Gomez, A.M., Valdivia, H.H., Cheng, H., Santana, L.F., Lederer, W.J., 1997, Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276, 800-806
7. Wang, S.Q., Song, L.-S., Lakatta, E.G., Cheng, H., 2001, Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature 410, 592-596
8. Pan, Z., Yang, D., Nagaraj, R.Y., Nosek, T.A., Nishi, M. Takeshima, H., Cheng, H., Ma, J., 2002, Dysfunction of store-operated Ca2+ channel in muscle cells lacking mg29 gene. Nature Cell Biol. 4, 379-383
9. Wang, S.Q., Stern, M.D., Ríos, E., Cheng, H., 2004,The quantal nature of ca2+ sparks and in situ operation of the ryanodine receptor array in cardiac cells. Proc. Natl. Acad. Sci. USA 101, 3979-3984
10. Wang, S.Q., Wei, C.L., Gao, G. L., Brochet, D., Shen, J.X., Song, L.S., Wang, W., Yang, D.M., Cheng, H., 2004, Imaging microdomain Ca2+ in muscle cells. Circ. Res. 94, 1011-1022 (invited review)
11. Wang, W., Zhu, W., Wang, S. Q., Yang, D. M., Crow, M. T., Xiao, R. P., Cheng, H., 2004, Sustained b1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circ. Res. 95,798-806.
12. Xu, X., Yang, D., Ding, J., Wang, W., Chu, P. H., Dalton, N. D., Wang, H. Y., Bermingham, J. R., Jr., Ye, Z., Liu, F., Rosenfeld, F. G., Manley, J. L., Ross J., Jr., Chen, J., Xiao, R.-P., Cheng, H., Fu, X. D., 2005, ASF/SF2-regulated postnatal reprogramming of CaMKIId alternative splicing modulates excitation-contraction coupling in cardiac muscle. Cell. 120, 59-72
13. Brochet, D. X. P., Yang, D., Di Maio, A., Lederer, W. J., Franzini-Armstrong, C., Cheng, H., 2005, Calcium blinks: Rapid nanoscopic store calcium signaling. Proc. Natl. Acad. Sci. USA, 102, 3099-3104
14. Ouyan, K., Wu, C. H., Cheng, H., 2005, Ca2+-induced Ca2+ release in sensory neurons: Low-gain amplification confers intrinsic stability. J. Biol. Chem. 280, 15898-15902
15. Ouyang, K., Zheng, H., Qin, X., Zhang, C., Yang, D., Wang, X., Wu, C., Zhou, Z., and Cheng, H., 2005, Ca2+ sparks and secretion in dorsal root ganglion neurons. Proc. Natl. Acad. Sci. USA. 102:12259-12264
16. Song, L-S, Sobie, EA, McCulle, S, Lederer, WJ, Balke, CW, Cheng, H., 2006, Orphaned ryanodine receptors in the failing heart. Proc. Natl. Acad. Sci. USA. 103: 4305-4310